Jennifer R. Brown, MD, PhD

 Frontline CLL [chronic lymphocytic leukemia] treatment has become quite effective. But patients who are at high risk for early failure or Richter syndrome appear to be a subset of those who have deletion 17p or 

 aberrancy and those with complex karyotype. Fortunately, a subset of both of those groups will do quite well, even with a single-agent BTK [Bruton tyrosine kinase] inhibitor, while another subset may develop Richter quite early. We don’t know how to figure out which is which, unfortunately.

There is a lot of interest for this population in looking at combination regimens, particularly BTK inhibitor with BCL2 inhibitor, plus or minus an anti-CD20. The idea is that if we give 2 potent agents together, the likelihood of early resistance will be reduced. Mathematically, it’s harder for the CLL to be resistant to 2 drugs rather than 1. For example, the German CLL Study Group has an ongoing study, CLL2-GiVe, looking at ibrutinib with venetoclax and obinutuzumab, monitoring for undetectable MRD [minimal residual disease], and discontinuing therapy in the study of undetectable MRD. That remains a question that clearly needs more data to address. High-risk patients benefit particularly from continuous therapy vs how we can address time-limited therapy for these patients.

The CLL14 study with time-limited therapy with venetoclax and obinutuzumab has about a 3-year progression-free survival of 60% for the 17p subgroup, whereas frontline single-agent ibrutinib in the NHLBI [National Heart, Lung, and Blood Institute] study had a 6-year progression-free survival of 60%. That has led many of us at present to use continuous BTK inhibitors for these patients. However, the idea of driving them into deeper remissions achieving undetectable MRD is appealing. The question is, can we actually stop therapy? If we do stop therapy, should we monitor for MRD and then re-treat early? Those are some key research questions. These may also be patients who, down the line, would perhaps be early candidates for CAR [chimeric antigen receptor] T-cell therapy when or if we start to see better tolerability as well as prolonged efficacy of CAR T cell. For example, a patient is on a BTK inhibitor, achieves a deep remission, still has residual disease, and then has what by then would hopefully be a safe and effective cellular therapy for consolidation, with the goal of a longer-term remission.

Ultimately, we’re all eagerly awaiting the head-to-head data comparing next-generation BTK inhibitors with ibrutinib in CLL. We did hear about a month ago by a press release that the data from the ELEVATE-RR trial will soon be available and that it did meet its primary end point of noninferiority for progression-free survival for acalabrutinib compared with ibrutinib and a decreased rate of atrial fibrillation with acalabrutinib. As a reminder, this is the head-to-head trial comparing acalabrutinib with ibrutinib in relapsed patients with deletion 17p or deletion 11q, the results of which have been eagerly awaited and should have quite mature follow-up when we see there are data, hopefully later this year. There is also an ongoing relapsed trial with zanubrutinib comparing zanubrutinib head-to-head with ibrutinib in CLL, but those data are still further off.

Videos

The shortcomings physicians face in combatting CLL (chronic lymphocytic leukemia) are discussed, in addition to what the high-level updates from the ELEVATE-RR press release may reveal regarding future treatments for CLL. 

Unmet Needs in Frontline Treatment of CLL 

My practice has been to favor using a next-generation BTK [Bruton tyrosine kinase] inhibitor initially in patients who will be at high risk for complications with ibrutinib. If a patient is started on ibrutinib and develops intolerance, there is the possibility to switch that patient from ibrutinib to the next-generation inhibitor. We do have some data, prospective data, looking at that transition for patients who are intolerant to ibrutinib to move to acalabrutinib. Only about 40% of patients experienced a recurring AE [adverse event] in that setting. It was the same or generally lower grade, and discontinuation was about 10%. It suggested that you can often sustain patients on acalabrutinib, even when they’ve been intolerant to ibrutinib.

I often will try to give patients a break, though, if they have had a good remission to ibrutinib, if they’ve been on it for a couple of years and their disease is controlled but now they have an adverse event, I like to give them time to recover if their disease is stable and then reevaluate later. Sometimes I’ll switch classes knowing that I can go back to a BTK inhibitor later.

Jennifer R. Brown, MD, PhD, suggests alternative treatments for patients who experience severe adverse-events from ibrutinib. 

Advice for Ibrutinib-Intolerant Patients 

Ibrutinib has been associated with significant adverse effects, including in the frontline setting, where some real-world data demonstrated a 40% discontinuation rate after a median of just 6 months on therapy. Even in RESONATE-2, the randomized trial, we have a 40% discontinuation rate after 4 years. This is because of a variety of adverse effects. Joint pains and arthralgias can be quite bothersome for frontline patients and lead to many discontinuations. There are also cardiac events, particularly atrial fibrillation and hypertension. Bleeding events also can be a major issue. We still don’t have head-to-head data comparing acalabrutinib with ibrutinib in terms of these adverse events, but a number of studies that have suggested that it may be better tolerated in this regard.

At ASH [American Society of Hematology Annual Meeting], a summary of 4 trials that included acalabrutinib monotherapy arms was presented with a particular focus on cardiovascular adverse effects. The overall incidence of any cardiac adverse events was 17%, with the most common being atrial fibrillation or flutter, which was seen in only 5%. The next 2 were tachycardia and palpitations, not particularly real events. The great majority of patients were able to remain on acalabrutinib despite a cardiac event, with a less-than-1% discontinuation rate due to the cardiac event. The rate of cardiac events over time also appeared relatively constant. We know with ibrutinib that there is an initial peak of atrial fibrillation in the first 6 months in which the relative risk is highest. With ongoing use, there is a continuing low rate of recurrent atrial fibrillation. There was also a meta-analysis of 27 studies presented at ASH that demonstrated significantly lower rates of any grade and grade 3 hypertension as well as any grade and grade 3 atrial fibrillation, with acalabrutinib compared with ibrutinib.

At the same time, we heard data from [The University of Texas] MD Anderson [Cancer Center] suggesting that the majority of patients on ibrutinib do develop worsened or new hypertension over time and that this is associated with other cardiac events, such as heart attacks and strokes. The summary of these data strongly suggests that for patients with underlying cardiac disease, there is a definite reason to prefer acalabrutinib. That’s certainly been my own personal practice for some time.

We also have data from the Alliance [North American Intergroup Study A041202] trial. In particular, they show that with increasing age, the toxicity of ibrutinib becomes more apparent. The treatment-related mortality over 3 years with ibrutinib, in both the ibrutinib and the ibrutinib-rituximab arms in the Alliance trial, was 7%, which is much higher than what was seen in the younger patient population in the ECOG trial. Increasing age is a reason to favor acalabrutinib over ibrutinib. The bleeding risks are not so clear. Most studies continue to show a significant rate of low-grade bleeding and bruising with acalabrutinib on the order of 40%, similar to ibrutinib. The major hemorrhage rate is usually around 3% or 4% in these studies, which is similar to ibrutinib. I remain hesitant about either BTK [Bruton tyrosine kinase] inhibitor in a patient who has had significant bleeding problems.

What if zanubrutinib gets approved? That’s a little complicated. We don’t have a lot of long-term follow-up data on zanubrutinib. In general, the adverse-event profile seems improved compared with ibrutinib and may be similar to acalabrutinib. We do…have head-to-head data with zanubrutinib compared with ibrutinib. That’s the first head-to-head trial that has been published, and there is a significant decrease in the rate of atrial fibrillation, from 15% with ibrutinib to 2% with zanubrutinib, as well as trends toward less hypertension and less edema. You do see more neutropenia with zanubrutinib, but in my experience, that’s been pretty manageable.

A switch between acalabrutinib and zanubrutinib is still challenging. We have longer follow-up data with acalabrutinib, but we actually have head-to-head data comparing zanubrutinib to ibrutinib. By the time zanubrutinib gets approved, we’ll likely have the head-to-head acalabrutinib data as well, which provides a further point of comparison. My personal anecdotal experience has been that zanubrutinib has even fewer symptomatic adverse effects than acalabrutinib. For example, you still have some patients who will get significant arthralgias with acalabrutinib, which I haven’t ever seen with zanubrutinib. For that reason, for example, zanubrutinib has now been listed in the NCCN [National Comprehensive Cancer Network] Guidelines who have been intolerant to ibrutinib and acalabrutinib in a relapse setting.

Citing results from recent trials, Jennifer R. Brown, MD, PhD, compares patient tolerability levels of ibrutinib, zanubrutinib, and acalabrutinib. 

Tolerability of Ibrutinib, Zanubrutinib, and Acalabrutinib 

BTK [Bruton tyrosine kinase] inhibitors have become a mainstay of therapy for CLL [chronic lymphocytic leukemia] over the last 5 to 10 years. The frontline use began following the randomized trial RESONATE-2, which looked at the first-in-class drug, ibrutinib, compared with chlorambucil in previously untreated patients of older age with CLL. Now we have the 5-year follow-up of that study, and the progression-free survival for those patients is about 70%, although there’s also been a 40% discontinuation rate, primarily because of adverse events. We know that these include cardiac adverse events, bleeding, infections, sometimes cytopenias, as well as arthralgias. The RESONATE-2 study was followed up by multiple randomized trials that have compared ibrutinib with more standard frontline chemotherapy immunotherapy regimens.

We have the Alliance North American Intergroup Study A041202, which looked at patients over age 65, previously untreated, who were randomized between single-agent ibrutinib, ibrutinib-rituximab, and bendamustine-rituximab. That study showed a significant progression-free survival benefit for both the ibrutinib and ibrutinib-rituximab arms, although no difference in overall survival. Of note, there was no difference with the addition of rituximab compared with single-agent ibrutinib.

The ECOG-E1912 study looked at a younger patient population, under age 70, and randomized them between ibrutinib-rituximab and FCR [fludarabine, cyclophosphamide, rituximab] and also found a significant progression-free survival benefit. In both studies, most of the benefit is driven by the higher-risk subgroups of CLL, in particular the unmutated 

 group had similar outcomes with all the regimens. Ibrutinib was also studied in combination with obinutuzumab compared with obinutuzumab-chlorambucil, and again had a very significant improvement in progression-free survival.

Since then there has been the development of next-generation still-covalent BTK inhibitors that also bind covalently to cysteine 481. The first of those has been acalabrutinib, which is now an approved CLL therapy in any line of therapy, including in the front line. That was on the basis of the ELEVATE TN treatment-naïve randomized trial, which compared acalabrutinib, acalabrutinib-obinutuzumab, and obinutuzumab-chlorambucil and showed significant benefit for both the acalabrutinib arms compared with the obinutuzumab-chlorambucil. Interestingly, there was also a 6% improvement in progression-free survival with the addition of obinutuzumab to acalabrutinib, although this was not a planned comparison. Further follow-up will be needed to further that. With the approval of both these agents in the frontline setting, we have a choice of BTK inhibitors for patients with CLL. There’s also another ongoing randomized trial comparing zanubrutinib, another covalent next-generation more specific BTK inhibitor to bendamustine-rituximab, also expected to eventually lead to approval in a frontline setting for zanubrutinib.

Jennifer R. Brown, MD, PhD, highlights newly FDA approved Bruton’s tyrosine kinase inhibitor (BTKi) monotherapy therapies for the treatment of CLL (chronic lymphocytic leukemia). 

Jennifer R. Brown, MD, PhD | Authors

Articles

Unmet Needs in Frontline Treatment of CLL

Advice for Ibrutinib-Intolerant Patients

Tolerability of Ibrutinib, Zanubrutinib, and Acalabrutinib

Approved BTKi Frontline Treatments for CLL